Genome-Informed Targeted Therapy for Osteosarcoma.
Genome-Informed Targeted Therapy for Osteosarcoma.
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DOI：
10.1158/2159-8290.cd-17-1152
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发表时间：
2019-01
期刊：
影响因子：
28.2
通讯作者：
Sweet-Cordero EA
中科院分区：
文献类型：
--
作者：
Sayles LC;Breese MR;Koehne AL;Leung SG;Lee AG;Liu HY;Spillinger A;Shah AT;Tanasa B;Straessler K;Hazard FK;Spunt SL;Marina N;Kim GE;Cho SJ;Avedian RS;Mohler DG;Kim MO;DuBois SG;Hawkins DS;Sweet-Cordero EA
骨肉瘤（OS）是一种高度侵袭性的癌症，其治疗方法30多年来基本没有变化。OS的特点是广泛和反复的体细胞拷贝数改变（SCNAs）和结构重排。相比之下，很少发现蛋白质编码基因的复发性点突变，这表明SCNAs内的基因是该疾病的关键致癌驱动因素。在OS病例中，scna和结构重排是高度异质性的，这表明需要一种基因组知情的靶向治疗方法。为了确定患者特异性的候选驱动因素，我们使用了一种简单的启发式方法，该方法基于拷贝数扩增的程度和等级顺序（通过全基因组测序鉴定）以及RNAseq鉴定的基因表达变化。利用患者来源的肿瘤异种移植物，我们证明了针对患者特异性体细胞拷贝数改变导致肿瘤负担显著减少，为基因组知情的OS治疗提供了路线图。
Osteosarcoma (OS) is a highly aggressive cancer for which treatment has remained essentially unchanged for over 30 years. OS is characterized by widespread and recurrent somatic copy-number alterations (SCNAs) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identified, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across OS cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specific candidate drivers, we used a simple heuristic based on degree and rank order of copy number amplification (identified by Whole Genome Sequencing) and changes in gene expression as identified by RNAseq. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specific somatic copy number alterations leads to significant decrease in tumor burden, providing a roadmap for genome-informed treatment of OS.